Abstract Breathing exercises are categorized as a mind-body practice. One in ten adults in the U.S. use breathing exercises for health purposes. Slow breathing exercises are commonly used for stress reduction. Higher stress is associated with higher cardiovascular risk. Effective and standardized breathing interventions for stress reduction have not been developed or well-studied. For centuries, mind-body practitioners have proposed that, in addition to breathing slowly, extending the length of exhale relative to inhale increases the dose of relaxation. Few studies have tested this belief. The aim of this proposal is to examine if slow breathing while extending the exhale time relative to the inhale time increases physiological and psychological relaxation. The slow breathing exercises to be studied are based on breathing techniques from yoga. The R61 grant phase will consist of a 12-week study among healthy adults randomized to daily slow breathing exercises of: (1) exhale greater than inhale versus (2) exhale equal to inhale in length. The R33 grant phase will examine the two slow breathing exercises for 12 weeks among a clinical population with elevated physiological and psychological stress. Results from the R61 phase, data from our prior research, and other published studies will be used to inform selection of this clinical population. The R33 phase will determine if relaxation produced by breathing exercises has different effects among patients with higher stress than the general healthy population. The R61 and R33 grants will have the same study aims. The first aim of the studies will be to compare 12 weeks of slow breathing with exhale greater than inhale on physiological stress as measured through autonomic tone. The second aim will be to compare changes in psychological stress as measured through validated stress and anxiety questionnaires. The final and third aim will be to measure the correlation between changes in physiological and psychological stress. This project will test if specific breathing techniques produce measurable and meaningful differences in stress in both healthy and disease populations. Because stress reduction is considered the major mechanism of mind-body practices, these studies will advance the field of mind-body science.